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First published online 30 May 2006
doi: 10.1242/jcs.02971
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Research Article |
results in altered trafficking of AQP2 and in nephrogenic diabetes insipidus
1 Department of Medicine/Nephrology, Emory University, Atlanta, GA 30322, USA and Atlanta Veterans Affairs Medical Center, Atlanta, GA 30033, USA
2 Department of Medicine/Nephrology, University of Texas Health Science Center San Antonio, and South Texas Veterans Health Care System, Audie Murphy Division, San Antonio, TX 78229, USA
* Author for correspondence (e-mail: jgooch{at}emory.edu)
Accepted 7 March 2006
The serine/threonine phosphatase calcineurin is an important signaling molecule involved in kidney development and function. One potential target of calcineurin action is the water channel aquaporin 2 (AQP2). In this study, we examined the effect of loss of calcineurin A
(CnA) on AQP2 function in vivo. CnA null mice were found to have defective post-natal urine-concentrating ability and an impaired urine-concentrating response to vasopressin. Expression of AQP2 is normal but, paradoxically, vasopressin-mediated phosphorylation of the channel is decreased compared with wild-type littermates and there is no accumulation of AQP2 in the apical membrane. Calcineurin protein and activity was found in innermedullary collecting duct vesicles, and loss of calcineurin expression and activity was associated with a loss of AQP2 in the vesicle fraction. As such, the lack of vasopressin-mediated phosphorylation of AQP2 might be the result of a defect in normal trafficking of AQP2 to apical-targeted vesicles. Likewise, treatment of wild-type mice with cyclosporin A to inhibit calcineurin produces a similarly impaired urine-concentrating response to vasopressin and alterations in AQP2 phosphorylation and trafficking. These experiments demonstrate that, CnA is required for normal intracellular trafficking of AQP2 and loss of calcineurin protein or activity disrupts AQP2 function.
Key words: Cyclosporin A, AQP2 trafficking, Calcineurin A-alpha knockout mouse
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